Controlled release composition

ABSTRACT

A composition for controlled delivery of at least one active substance into an aqueous medium by erosion at a preprogrammed rate of at least one surface of the composition, comprising a matrix comprising the active substance, the matrix being erodible in the aqueous medium in which the composition is to be used, and a coating having at least one opening exposing at least one surface of said matrix, the coating comprising a first cellulose derivative which has thermoplastic properties and which is substantially insoluble in the aqueous medium in which the composition is to be used, and at least one of a second cellulose derivative which is soluble or dispersible in water, a plasticizer, and a filler. The coating is a coating which crumbles and/or erodes upon exposure to the aqueous medium such as a body fluid. The first cellulose derivative may be, e.g., ethylcellulose, cellulose acetate, cellulose propionate or cellulose nitrate, and the second cellulose derivative may be, e.g. methylcellulose, carboxymethylcellulose or salts thereof, cellulose acetate phthalate, microcrystalline cellulose, ethylhydroxyethylcellulose, ethylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose or hydroxymethylpropylcellulose.

FIELD OF THE INVENTION

The present invention relates to a composition for controlled deliveryof an active substance into an aqueous medium.

BACKGROUND OF THE INVENTION

It is known to obtain sustained release of an active substance, e.g. apharmaceutically active powder, by embedding it in a matrix of aninsoluble substance from which the active substance will graduallydiffuse. Sustained release of an active substance contained in a tabletcore may also be achieved by applying to the core a semi-permeablecoating through which water and dissolved active substance may diffuseor an insoluble coating provided with a hole through which the activesubstance is released. Gradual release of an active substance mayfurthermore be obtained by microencapsulating particles of an activesubstance in one or more layers of film which may be of different types,e.g. of a type which mediates diffusion of the active substance orrelease thereof in the intestines.

These conventional ways of providing sustained release of an activesubstance have certain drawbacks, in that it is difficult to maintain aconstant concentration of the active substance, for example a constantconcentration of a pharmaceutically active substance in plasma for theentire period when the dosage form is present in the body. Inparticular, this may be the problem with drugs which have a briefhalf-life in the body. Furthermore, the penetration of water throughdiffusion coatings may cause hydrolysis of active substances which areunstable in an aqueous environment.

WO 89/09066 discloses a composition for controlled delivery of an activesubstance into an aqueous phase by erosion at a substantially constantrate of a surface or surfaces of the composition, the compositioncontaining a) a matrix of a crystalline polyethylene glycol polymer witha molecular weight of at least 20,000 daltons, b) at least one non-ionicemulsifier dispersed in the polyethylene glycol matrix in an amount of2-50% by weight of the crystalline polymer and the non-ionic emulsifier,the non-ionic emulsifier having at least one domain which is compatiblewith the polyethylene glycol polymer and being selected from fatty acidesters and fatty alcohol ethers, and c) at least one active substancesubstantially homogeneously dispersed in the polyethylene glycol matrixand/or located in geometrically well-defined zones within thecomposition, the non-ionic emulsifier and/or the active substancereducing the water affinity of domains between grains and in cracks inthe crystalline polymer matrix and in the crystalline polymer matrixitself, thereby substantially eliminating water diffusion in theinterface between the polymer crystals, so that the erosion ispredominantly effected by the dissolving action of an aqueous medium ona surface or surfaces of the composition exposed to the medium.

Other controlled release compositions based on this principle aredisclosed in WO 91/04015, which relates to compositions that provide aregulated non-initial burst release of an active substance at apredetermined time.

The present invention is a further development based on the inventionsdisclosed in WO 89/09066 and WO 91/04015. In particular, the presentinvention provides a novel coating based on certain cellulosederivatives, the coating being particularly suitable for controlledrelease compositions with a matrix containing an active substance, e.g.a matrix such as that disclosed WO 89/09066.

SUMMARY OF THE INVENTION

The present invention thus relates to a composition for controlleddelivery of at least one active substance into an aqueous medium byerosion at a preprogrammed rate of at least one surface of thecomposition, comprising

-   i) a matrix comprising the active substance, the matrix being    erodible in the aqueous medium in which the composition is to be    used, and-   ii) a coating having at least one opening exposing at least one    surface of said matrix, the coating comprising    -   a) a first cellulose derivative which has thermoplastic        properties and which is substantially insoluble in the aqueous        medium in which the composition is to be used,    -   and at least one of    -   b) a second cellulose derivative which is soluble or dispersible        in water,    -   c) a plasticizer, and    -   d) a filler,        said coating being a coating which crumbles and/or erodes upon        exposure to the aqueous medium, in particular a body fluid, at a        rate which is equal to or slower than the rate at which the        matrix erodes in the aqueous medium, allowing exposure of said        surface of the matrix to the aqueous medium to be controlled.

The combination of the matrix and the active substance must besubstantially impenetrable to fluids of the aqueous phase, for examplebody fluids present where the composition of the invention is introducedinto the body (e.g. in the gastrointestinal tract, including the rectum,in the vagina or subcutaneously) or into a body cavity via a catheter(e.g. the urinary bladder, the gall bladder, the uterus, a centralnervous system cavity, infectious/malignant/post-operative cavities,etc.), in order to avoid degradation of the active substance residing inthe matrix due to the action of water in the case of an activesub-stance which is susceptible to hydrolysis. The inclusion of theactive substance in a matrix into which water diffusion is substantiallyeliminated will thus impart stability to the composition, so that theactive substance will remain active even when the composition has beenexposed to body fluids or other fluids for a period of time. As thefluids can only act on the surface of a matrix of this type, the activesubstance embedded therein is only exposed to the fluids in questionwhen it is released or immediately prior to its release from the matrix.A matrix of a type which is substantially impenetrable to water willtherefore ensure the stability of the active substance in the matrixuntil the time when the active substance is actually released, and willalso ensure that release of the active substance takes place at acontrolled and reproducible rate, since the release proceeds graduallyfrom the surface or surfaces of the matrix exposed to the fluids inquestion.

Due to the controlled release of the active substance from thecomposition of the invention, it is possible to obtain a substantiallyconstant rate of release or a controlled pulsatile release of the activesubstance over a specific period of time. Adherence to a strict dosageregimen, e.g. requiring administration of a drug at set intervals up toseveral times a day, may therefore be dispensed with. Furthermore, it ispossible to include two or more different active substances in thecomposition of the invention, adapted to be released at differentconcentrations and/or intervals, thus making it easier for patients tofollow a prescribed regimen.

An additional advantage of the composition of the invention is that itmay be produced by relatively simple and inexpensive methods, e.g. byextrusion, as will be explained in more detail below. Furthermore, thecomposition allows for the incorporation of high concentrations of theactive substance relative to the composition's size. This is obviously agreat advantage, notably when the composition is to be used for thedelivery of a pharmaceutically active substance, since it allows for thedelivery of the required amount of the active substance without thecomposition being unnecessarily large. Compositions of the invention inwhich the matrix contains a surface active agent may furthermore be usedfor the delivery of sparingly soluble or non-soluble pharmaceuticalpowders which can otherwise be difficult to administer, since suchsubstances are compatible with the lipophilic domains of the surfaceactive agent.

DETAILED DISCLOSURE OF THE INVENTION

A suitable matrix for use in the compositions of the invention is one ofthe type described in WO 89/09066 or WO 91/04015, to which reference ismade and which are incorporated herein by reference, i.e. a matrixcontaining a crystalline polyethylene glycol polymer with a molecularweight of at least 20,000 daltons in which at least one non-ionicemulsifier is dispersed. A preferred non-ionic emulsifier for use in thematrix is polyethylene glycol stearate. Preferred polyethylene glycolsfor use in the matrix have a molecular weight in the range of20,000-35,000 daltons. However, while WO 89/09066 discloses matricescontaining a crystalline polyethylene glycol polymer with a molecularweight of at least 20,000 daltons, interesting compositions according tothe present invention also include those in which the matrix contains apolyethylene glycol polymer with a molecular weight of less than 20,000daltons.

The crystalline polymer matrix must have a melting point which is abovethe temperature of the aqueous medium in which the composition of theinvention is to be used. Thus, the polymer(s) employed in the matrixwill suitably have a melting point of about 20-120° C., typically about30-100° C., more typically about 40-80° C., depending on how thecomposition is to be employed. In particular, when the composition ofthe invention is used for the delivery of a drug for human or veterinaryuse, the matrix will suitably have a melting point of about 40-80° C.

Alternatively, the matrix may be of the same basic type as the coating,i.e. comprising a thermoplastic and substantially insoluble cellulosederivative, e.g. ethylcellulose, as well as at least one other cellulosederivative and/or a plasticizer and/or a filler. In a matrix of thistype the cellulose derivative(s), the plasticizer and the filler may beselected from the corresponding cellulose derivatives, plasticizers andfillers described below in connection with the coating. The specificcompounds and amounts thereof used for the matrix in this case would ofcourse have to be adapted to the particular coating used for any givencomposition, so that the desired erosion pattern and release of theactive substance into the aqueous medium is obtained.

As mentioned above, the coating is one which crumbles and/or erodes uponexposure to an aqueous medium at a rate which is equal to or slower thanthe rate at which the matrix erodes in the same aqueous medium. Exposureof the surface of the matrix to the aqueous medium is therebycontrolled, so that the desired release profile of the active substancein the matrix is obtained.

As mentioned above, the first cellulose derivative is one which hasthermoplastic properties, i.e. it softens upon heating. The firstcellulose derivative may be a cellulose ether which, when heated, isshapeable by molding or extrusion, including injection molding, blowmolding and compression molding. A preferred cellulose ether isethylcellulose, typically an ethylcellulose with an ethoxyl content inthe range of 44.5-52.5%, such as in the range of 45.0-46.5% or in therange of 48.0-49.5%. Typical commercially available ethylcelluloseproducts have an ethoxyl content of 45.0-49.5%, corresponding to2.25-2.58 ethoxyl groups per anhydroglucose unit.

The first cellulose derivative may furthermore be selected from thegroup consisting of cellulose acetate, cellulose propionate andcellulose nitrate.

The second cellulose derivative is typically selected from the groupconsisting of methylcellulose, carboxymethylcellulose and salts thereof,cellulose acetate phthalate, microcrystalline cellulose,ethylhydroxyethylcellulose, ethylmethylcellulose, hydroxyethylcellulose,hydroxyethylmethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxymethylcellulose andhydroxymethylpropylcellulose. When the second cellulose derivative is asalt of carboxymethylcellulose, the salt will typically be selected fromthe group consisting of alkali metal and alkaline earth metal salts.

Currently preferred compounds for use as the second cellulose derivativepharmaceutical quality hydroxypropylmethylcellulose orcarboxymethylcellulose.

The use of a plasticizer will often be desirable in order to improve theprocessibility of the ethylcellulose or other first cellulosederivative, e.g. to adjust the softening point of the ethylcellulose.When the coating contains a plasticizer, this is typically selected fromthe group consisting of phosphate esters; phthalate esters; amides;mineral oils; fatty acids and esters thereof with polyethylene glycol,glycerin or sugars; fatty alcohols and ethers thereof with polyethyleneglycol, glycerin or sugars; and vegetable oils. Suitable fatty alcoholsare cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcoholand myristyl alcohol.

The plasticizer may also be a non-ionic surfactant, e.g. a non-ionicsurfactant is selected from the group consisting of diacetylatedmonoglycerides, diethylene glycol monostearate, ethylene glycolmonostearate, glyceryl monooleate, glyceryl monostearate, propyleneglycol monostearate, macrogol esters, macrogol stearate 400, macrogolstearate 2000, polyoxyethylene 50 stearate, macrogol ethers,cetomacrogol 1000, lauromacrogols, nonoxinols, octoxinols, tyloxapol,poloxamers, polyvinyl alcohols, polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, sorbitanmonolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitantristearate and sucrose esters.

The plasticizer may further be selected from the group consisting ofmethyl abietate, acetyl tributyl citrate, acetyl triethyl citrate,diisooctyl adipate, amyl oleate, butyl ricinoleate, benzyl benzoate,butyl and glycol esters of fatty acids, butyl diglycol carbonate, butyloleate, butyl stearate, di(β-methoxyethyl) adipate, dibutyl sebacate,dibutyl tartrate, diisobutyl adipate, dihexyl adipate, triethyleneglycol di(2-ethyl butyrate), polyethylene glycol di(2-ethyl hexoate),diethylene glycol monolaurate, monomeric polyethylene ester,hydrogenated methyl ester of rosin, methoxyethyl oleate, butoxyethylstearate, butyl phthalyl butyl glycolate, glycerol tributyrate,triethylene glycol dipelargonate, β-(p-tert.-amylphenoxy)ethanol,β(p-tert.-butylphenoxy)ethanol, β-(p-tert.-butylphenoxyethyl)acetate,bis(β-p-tert.-butylphenoxydiethyl)ether, camphor, Cumar W-1, Cumar MH-1,Cumar V-1, diamyl phthalate, (diamylphenoxy) ethanol, diphenyl oxide,technical hydroabietyl alcohol, beckolin, benzene hexahydrochloride,Clorafin® 40, Piccolastic® A-5, Piccolastic® A-25, Flexol B-400,Glycerol α-methyl α-phenyl ether, chlorinated naphthalene, HB-40,monoamylphthalate, Nevillac 10. Q-nitro-diphenyl and Paracril 26.

When the coating contains a filler, the filler is preferably aconventional tablet or capsule excipient such as a diluent, a binder, alubricant or a disintegrant.

Diluents for use as fillers may be selected from the group consisting ofdicalcium phosphate, calcium sulfate, sugars, including lactose andsucrose, dextrin, cellulose, cellulose derivatives, kaolin, mannitol,dry starch, glucose, sorbitol, and inositol.

Suitable binders are those selected from the group consisting of acacia,sodium alginate, starch, gelatin, saccharides, including glucose,sucrose, dextrose and lactose, molasses, extract of Irish moss, panwargum, ghatti gum, mucilage of isapol husk, carboxymethylcellulose,methylcellulose, veegum, larch arabolactan, polyethylene glycols,ethylcellulose, water, alcohols, waxes, and polyvinylpyrrolidone.

Suitable lubricants are those selected from the group consisting oftalc, magnesium stearate, calcium stearate, stearic acid, hydrogenatedvegetable oils, sodium benzoate, sodium chloride, leucine, carbowax4000, magnesium lauryl sulfate, and colloidal silicon dioxide.

Suitable disintegrants are those selected from the group consisting ofstarches, clays, cellulose derivatives including croscarmellose, gums,algins, combinations of hydrocarbonates with weak acids, crospovidone,sodium starch glycolate, agar, cation exchange resins, citrus pulp,veegum HV, natural sponge, and bentonite.

Compositions according to the invention may further comprise a watersoluble antioxidant, a lipid soluble anti-oxidant and/or a preservativein either the matrix or the coating. Suitable antioxidants andpreservatives may be selected from the group consisting of ascorbylpalmitate, benzoic acid, benzyl hydroxybenzoate, bronopol, butylhydroxybenzoate, butylated hydroxyanisole, butylated hydroxytoluene,chlorbutol, cinnamic acid, dehydroacetic acid, diethyl pyrocarbonate,diphenyl, dodecyl gallate, ethoxyquin, ethyl gallate, ethylhydroxybenzoate, gallic acid, isoascorbic acid, methyl hydroxybenzoate,monothioglycerol, nordihydroguaiaretic acid, octyl gallate,pentachlorophenol, phenethyl alcohol, phenoxyethanol, phenylmercuricacetate, phenylmercuric borate, phenylmercuric nitrate, Q-phenylphenol,potassium metabisulphite, potassium sorbate, propyl gallate, propylhydroxybenzoate, sodium benzoate, sodium butyl hydroxybenzoate, sodiumdehydroacetate, sodium diacetate, sodium ethyl hydroxybenzoate, sodiumformaldehyde-sulphoxylate, sodium isoascorbate, sodium metabisulphite,sodium methyl hydroxybenzoate, sodium Q-phenylphenol, sodium propylhydroxybenzoate, sodium sulphite, anhydrous sodium sulphite, sorbicacid, sulphur dioxide, and thiodipropionic acid.

The coating may be designed so that its longitudinal erosion rate issubstantially the same as the longitudinal erosion rate of the matrix,whereby the matrix and the coating will erode longitudinally towards thecenter of the composition at substantially the same rate. Such a coatingwould be suitable for a rod-shaped composition having an opening in thecoating at each end. Thus, when the matrix has been completely eroded bythe aqueous medium, the coating will also be substantially completelyeroded. A composition having such a coating has the advantage of beingcompletely biodegraded upon release of the active substance.

The coating may also be in which, in the aqueous medium in which thecomposition is to be used, the coating does not completely crumble orerode before the matrix has completely eroded. A coating of this typewould remain more or less intact as long as it was supported by thematrix containing the active substance, but it would lack the ability toremain intact after erosion of the matrix, whereby it would thendisintegrate or crumble, so that it would not remain in e.g. a human oranimal for any significant amount of time after the complete erosion ofthe matrix and the release of the active substance.

The active substance to be delivered by the composition according to theinvention can be a drug for human or veterinary use, a vitamin or othernutritional supplement, a disinfectant, a deodorant or another substanceto be administered continuously in an aqueous environment.

The composition of the invention is especially suitable for the deliveryof an active substance which is a pharmaceutically active substance, inparticular a pharmaceutically active powder. The pharmaceutically activesubstance or substances included in the composition of the invention maybe selected from many therapeutic categories, in particular fromsubstances which may advantageously be administered orally, rectally,vaginally or subcutaneously, or administered to a body cavity (e.g. theurinary bladder, the gall bladder, the uterus, a central nervous systemcavity, infectious/malignant/post-operative cavities, etc.). Examples ofsuch substances are antimicrobial agents, analgesics, antiinflammatoryagents, counterirritants, coagulation modifying agents, diuretics,sympathomimetics, anorexics, antacids and other gastrointestinal agents,antiparasitics, antidepressants, antihypertensives, anticholinergics,stimulants, antihormones, central and respiratory stimulants, drugantagonists, lipid-regulating agents, uricosurics, cardiac glycosides,electrolytes, ergot and derivatives thereof, expectorants, hypnotics andsedatives, antidiabetic agents, dopaminergic agents, antiemetics, musclerelaxants, para-sympathomimetics, anticonvulsants, antihistamines,β-blockers, purgatives, antiarrhytmics, contrast materials,radiopharmaceuticals, antiallergic agents, tranquilizers, vasodilators,antiviral agents, and antineoplastic or cytostatic agents or otheragents with anticancer properties, or a combination thereof. Othersuitable active substances may be selected from contraceptives andvitamins as well as micro- and macronutrients.

The composition is in addition suitable for the delivery ofpolypeptides, for example hormones such as growth hormones, enzymes suchas lipases, proteases, carbohydrases, amylases, lactoferrin,lactoperoxidases, lysozymes, nanoparticles, etc., and antibodies. Thecomposition may also be employed for the delivery of microorganisms,either living, attenuated or dead, for example bacteria, e.g.gastrointestinal bacteria such as streptococci, e.g. S. faecium,Bacillus spp. such as B. subtilis and B. licheniformis, lactobacteria,Aspergillus spp., bifidogenic factors, or viruses such as indigenousvira, enterovira, bacteriophages, e.g. as vaccines, and fungi such asbaker's yeast, Saccharomyces cerevisiae and fungi imperfecti. Thecomposition may also be used for the delivery of active agents inspecialized carriers such as liposomes, cyclodextrines, nanoparticles,micelles and fats.

One of the uses for which the composition of the invention iswell-suited is the delivery of antimicrobial agents to the vagina.Examples of such agents are antifungals, for example imidazoleantifungals such as clotrimazole, econazol, ketoconazole and miconazole,polyene antifungal antibiotics such as nystatin, and antiprotozoals suchas metronidazole and ornidazole.

A pharmaceutically active powder to be administered by the compositionof the invention will suitably have a particle size of from about 0.1 μmto about 500 μm, typically from about 0.5 μm to about 300 μm, moretypically from about 1 μm to about 200 μm, especially from about 5 μm toabout 100 μm.

The active substance will suitably be present in an amount of up toabout 60%, typically up to about 50%, by weight of the composition. Anactive substance content of about 70% is contemplated to be the maximumcontent which still allows for a sufficient content of the crystallinepolymer matrix and the non-ionic emulsifier in the composition. Theactive substance may, on the other hand, be present in the compositionin much smaller amounts, depending on the nature and strength of theactive substance in question.

Diffusion of water into the composition is substantially limited to thesurface layer of the matrix, whereby any exposed matrix surfaces areeroded at a substantially constant and pH-independent rate. As a result,a substantially zero order release of the active substance is obtained,the term “zero order” referring to the fact that the release rate of theactive substance is substantially constant with time, when the activesubstance is substantially homogeneously distributed in the matrix. Inthe case of the active substance being located in geometricallywell-defined zones within the matrix, the result of the constant erosionrate of the matrix will be a strictly controlled pulsatile release ofthe active ingredient.

The geometric form of the composition is important for the obtainment ofthe above-mentioned controlled zero order or pulsatile release. Thus, ina preferred version of the invention, the composition of the inventionhas a geometric shape which enables a substantially constant surfacearea to become exposed during erosion of the matrix. The composition maythus e.g. have the shape of a cylindrical rod provided with a cellulosederivative-based coating of the type described above.

While the composition will typically be in the form of a rod orcylinder, it may also have another shape which allows the activesubstance to be released at the desired preprogrammed rate. The term“cylindrical rod” as used in the context of the present invention isunderstood to comprise not only those geometrical forms having asubstantially circular cross-section, but also other substantiallycylindrical forms, e.g. those having a somewhat flattened cross-section,for example a substantially oval or ellipse shaped cross-section.

It will also be understood by a person skilled in the art that thespecific finished form of the composition of the invention may comprisecertain minor modifications in order to facilitate the use of thecomposition in question. For example, a cylindrical rod-shapedcomposition for delivery of a pharmaceutical powder may have roundedends so as to avoid possible injury or discomfort when the compositionis introduced into the body.

As mentioned above, the active substance can be substantiallyhomogeneously dispersed in the crystalline polymer matrix, in which casea substantially zero order release of the active substance is obtained.Alternatively, a pulsatile release of the active substance may beobtained in a composition of the invention which comprises alternatinglayers. A pulsatile release may thus be obtained with a compositionhaving the above-mentioned shape of a cylindrical rod and comprisingalternating substantially transverse layers of 1) a layer comprising thecrystalline polymer matrix, and 2) a layer comprising the activeingredient. If desired, the active ingredient may also be dispersed inthe crystalline polymer matrix. In a composition comprising alternatinglayers, the alternating layers may comprise two or more different activesubstances.

These two release patterns (i.e. zero order and pulsatile) may also becombined so that a uniform release of one active substance (for exampleat a fairly low dosage level) alternates with the release in bursts ofthe same or another active substance (for example at a higher dosagelevel).

The composition of the invention may be produced by various methodswhich are either known per se in the pharmaceutical industry or which,for example, are used in the production of polymer-based materials,depending upon the desired embodiment and the materials employed in thecomposition in question. As mentioned above, one advantage of thecomposition according to the invention is that it may be produced bymethods which are relatively simple and inexpensive.

The composition may be produced by, for example, co-extrusion of thecoating with the matrix and the active substance, extrusion and dipcoating, injection molding and dip coating, or by extrusion or injectionmolding.

For the preparation of a composition having a matrix of a crystallinepolymer and a non-ionic emulsifier, these ingredients will typically bemixed while heating at a temperature sufficient to melt the polymer, andwhile stirring, so as to obtain a substantially homogeneous mixture. Inthe case of the active substance being included in the matrix, it mayeither be added to the molten mixture of the polymer and the non-ionicemulsifier or it may be added to the mixture prior to heating. Themolten mixture is then e.g. extruded or injected, as explained below.For the preparation of a composition for pulsatile release of the activesubstance, the active substance may conveniently be included in matrixmaterial, the mixture of the active substance and the matrix materialbeing e.g. extruded or injected in layers which alternate with layers ofthe matrix without the active substance.

For the production of a composition which has the shape of a cylindricalrod, the matrix material comprising the active substance may be injectedinto a pre-formed tube which forms the coating. Alternatively, acylindrical rod-shaped composition may be produced by injectingalternating layers comprising at least, respectively, the matrixmaterial and the active substance into said tube. A cylindricalrod-shaped composition may also be produced by, for example, extrudingthe matrix material with the active substance dispersed therein,followed by dip coating; or by co-extrusion of a) the matrix materialwith the active substance dispersed therein and b) the coating.

A cylindrical rod shaped composition may also be produced by injectionmolding, including two-component or multiple-component injectionmolding, of the coating and the matrix comprising the active substance.Injection molding is especially suitable for the coatings used accordingto the present invention. Typically, a cylinder which functions as acoating is produced in a first step around a solid core of e.g. steel,after which the matrix is produced in a second step or, alternatively,multiple steps, by injection of the matrix material after removal of thesteel core. This method has the advantage of being simple andwell-suited for mass production.

Production methods which involve co-extrusion are also advantageous, asthey are also simple and inexpensive methods suitable for massproduction. The rod or tube which is produced by co-extrusion orextrusion is then cut into smaller segments of an appropriate size. Thecomposition may then be finished, for example by rounding the ends ofthe individual cylindrical rods.

It will be clear to persons skilled in the art that the amount of activesubstance and the dimensions and specific form of the composition of theinvention will of course vary according to the nature of the activesubstance in question as well as the intended use of the composition.The particular dose to be administered to a person or animal when thecomposition is used for the delivery of a pharmaceutically active powderwill thus depend on such factors as the condition and age of the patientand the particular condition to be treated.

The present invention is further illustrated by the followingnon-limiting examples.

EXAMPLE 1

A composition according to the invention was prepared from the followingingredients:

% by weight Coating Ethylcellulose (Dow Chem. Co.) 50 (ethoxyl content45-46.5%) Hydroxymethylcellulose 20 Carboxymethylcellulose 5 Cetostearylalcohol 20 Titanium dioxide 5 Matrix Polyethylene glycol 35,000 50Polyethylene glycol 2000 10 stearate Potato starch 39 Tartrazine 1

The coating was prepared by first mixing the ethylcellulose with thehydroxymethylcellulose, carboxymethylcellulose and titanium dioxide,after which melted cetostearyl alcohol was added. After mixing in a highspeed dry mixer (Robot Coupe) for about 2 minutes, the mixture was driedin an oven at 100° C. for about 30 minutes. The mixture was then allowedto cool to room temperature, after which it had a suitable consistencyfor being fed into an injection moulding machine.

The matrix was prepared by first mixing the PEG 35,000, the potatostarch and the tartrazine together in a high speed dry mixer (RobotCoupe). The PEG 2000 stearate was then melted on a heating plate at atemperature of 100° C. and added to the mixture of the other 3ingredients while mixing. After mixing for 2 minutes the mixture wasallowed to cool to room temperature and was ready to be fed into aninjection moulding machine.

The composition was prepared by injection moulding (Arbourg Allrounder)using a single unit mould, resulting in a composition containing acylindrical inner matrix with dimensions of 4×12 mm and a coating withthickness of 0.5 mm.

Both the coating and matrix mixtures were easy to feed into theinjection moulding machine and performed well in the mould. An analysisof the dissolution of the composition prepared as above in a dissolutiontester (US-Paddle) with saline as an aqueous medium showed a zero orderrelease of the tartrazine in the matrix over a period of 12 hours. After24 hours the coating was slightly weakened and slightly eroded at thesurface.

The same composition was then taken orally by volunteers and isolated infeces after a transit time of 16-48 hours. (A total of 8 units withvarying passage times were evaluated). After passage through thegastrointestinal tract about 20-30% by weight of the coating of thecomposition had been eroded from its surface, and the coating was softand weak. It is believed that a longer passage time (longer retention inthe gastrointestinal tract) would result in the completeerosion/dissolution of the coating.

EXAMPLE 2

A composition according to the invention was prepared from the followingingredients:

% by weight Coating Ethylcellulose (Dow Chem. Co.) 50 (ethoxyl content45-46.5%) Hydroxymethylcellulose 17.5 Carboxymethylcellulose 7.5Cetostearyl alcohol 20 Titanium dioxide 5 Matrix Polyethylene glycol35,000 37 Polyethylene glycol 2000 10 stearate Potato starch 49Tartrazine 1 Hydroxymethylcellulose 3

The coating was prepared as described above in Example 1.

The matrix was also prepared as described above in Example 1, thehydroxymethylcellulose being mixed together with the PEG 35,000, thepotato starch and the tartrazine in the initial mixing step.

A composition having the same dimensions as that of Example 1 wasprepared as described in Example 1.

Also the coating and matrix mixtures of this Example were easy to feedinto the injection moulding machine and performed well in the mould. Ananalysis (using the method described in Example 1) of the dissolution ofthe composition showed a zero order release of the tartrazine in thematrix over a period of 28 hours. After 36 hours the coating wasslightly eroded and weak, as was the case with the composition ofExample 1. The erosion and weakening/softening of the coating afterpassage through the gastrointestinal tract of human volunteers was alsoof the same extent and character as observed with the coating of Example1.

1. A composition for controlled delivery of at least one activesubstance into an aqueous medium by erosion at a preprogrammed rate ofat least one surface of the composition, comprising i) a matrixcomprising the active substance, the matrix being erodible in theaqueous medium in which the composition is to be used, and ii) a coatinghaving at least one opening exposing at least one surface of saidmatrix, the coating comprising a) a first cellulose derivative which hasthermo-plastic properties and which is substantially insoluble in theaqueous medium in which the composition is to be used, and at least oneof b) a second cellulose derivative which is soluble or dispersible inwater, c) a plasticizer, and d) a filler, said coating being a coatingwhich crumbles and/or erodes upon exposure to the aqueous medium, inparticular a body fluid, at a rate which is equal to or slower than therate at which the matrix erodes in the aqueous medium, allowing exposureof said surface of the matrix to the aqueous medium to be controlled. 2.A composition according to claim 1 wherein any exposed matrix surfaceserode at a substantially constant rate.
 3. A composition according toclaim 1 wherein, in the aqueous medium in which the composition is to beused, the coating does not completely crumble or erode before the matrixhas completely eroded.
 4. A composition according to claim 1 in whichsaid first cellulose derivative is a cellulose ether which, when heated,is shapeable by molding or extrusion, including injection molding, blowmolding and compression molding.
 5. A composition according to claim 4in which the cellulose ether comprises at least one ethylcellulose.
 6. Acomposition according to claim 5 in which said ethyl-cellulose has anethoxyl content in the range of 44.5-52.5%.
 7. A composition accordingto claim 6 in which said ethyl-cellulose has an ethoxyl content in therange of 45.0-49.5%.
 8. A composition according to claim 1 in which saidfirst cellulose derivative is selected from the group consisting ofcellulose acetate, cellulose propionate and cellulose nitrate.
 9. Acomposition according to claim 1 in which said second cellulosederivative is selected from the group consisting of methylcellulose,carboxymethylcellulose and salts thereof, cellulose acetate phthalate,microcrystalline cellulose, ethylhydroxyethylcellulose,ethylmethylcellulose, hydroxyethylcellulose,hydroxyethylmethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxymethylcellulose andhydroxymethylpropylcellulose.
 10. A composition according to claim 9 inwhich said salt of carboxymethylcellulose is selected from the groupconsisting of alkali metal and alkaline earth metal salts.
 11. Acomposition according to claim 9 in which said second cellulosederivative is pharmaceutical quality hydroxypropylmethylcellulose.
 12. Acomposition according to claim 1 in which said plasticizer is selectedfrom the group consisting of phosphate esters; phthalate esters; amides;mineral oils; fatty acids and esters thereof with polyethylene glycol,glycerin or sugars; fatty alcohols and ethers thereof with polyethyleneglycol, glycerin or sugars; and vegetable oils.
 13. A compositionaccording to claim 12 in which said fatty alcohol is selected from thegroup consisting of cetostearyl alcohol, cetyl alcohol, stearyl alcohol,oleyl alcohol and myristyl alcohol.
 14. A composition according to claim1 in which said plasticizer is a non-ionic surfactant.
 15. A compositionaccording to claim 1 in which said filler is selected from conventionaltablet or capsule excipients.
 16. A composition according to claim 15 inwhich the filler is a diluent, a binder, a lubricant or a disintegrant.17. A composition according to claim 1 in which the matrix and/or thecoating further comprises a water soluble antioxidant, a lipid solubleantioxidant and/or a preservative.
 18. A composition according to claim1 in which the matrix comprises a crystalline polyethylene glycolpolymer and at least one non-ionic emulsifier dispersed in thepolyethylene glycol matrix in an amount of 2-50% by weight of thecrystalline polymer and the non-ionic emulsifier, the non-ionicemulsifier having at least one domain which is compatible with thepolyethylene glycol polymer and being selected from fatty acid estersand fatty alcohol ethers, the active substance being substantiallyhomogeneously dispersed in the polyethylene glycol matrix and/or locatedin geometrically well-defined zones within the matrix, the non-ionicemulsifier and/or the active substance reducing the water affinity ofdomains between grains and in cracks in the crystalline polymer matrixand in the crystalline polymer matrix itself, thereby substantiallyeliminating water diffusion in the interface between the polymercrystals, so that erosion of the matrix is predominantly effected by thedissolving action of the aqueous medium on any matrix surfaces exposedto the medium.
 19. A composition according to claim 18 in which thepolyethylene glycol polymer has a molecular weight of at least 20,000daltons.
 20. A composition according to claim 19 in which thepolyethylene glycol polymer has a molecular weight in the range of20,000-35,000 daltons.
 21. A composition according to claim 18 in whichthe polyethylene glycol polymer has a molecular weight of less than20,000 daltons.
 22. A composition according to claim 18 wherein thenon-ionic emulsifier is a polyethylene glycol stearate.
 23. Acomposition according to claim 1 wherein the matrix comprising theactive substance comprises d) a third cellulose derivative which hasthermoplastic properties and which is substantially insoluble in theaqueous medium in which the composition is to be used, and at least oneof e) a fourth cellulose derivative which is soluble or dispersible inwater, f) a second plasticizer, and g) a second 24.-27. (canceled)
 28. Amethod for producing a composition for controlled delivery of at leastone active substance into an aqueous medium by erosion at apreprogrammed rate of at least one surface of the composition, themethod of comprising forming, by means that include extrusion orinjection moulding, i) a matrix comprising the active substance, thematrix being erodible in the aqueous medium in which the composition isto be used, and ii) a coating having at least one opening exposing atleast one surface of said matrix, the coating comprising a) a firstcellulose derivative which has thermoplastic properties and which issubstantially insoluable in the aqueous medium in which the compositionis to be used, and at least one of b) a second cellulose derivativewhich is soluable or dispersible in water, c) a plasticizer, and d) afiller, said coating being a coating which crumbles and/or erodes uponexposure to the aqueous medium, in particular a body fluid, at a ratewhich is equal to or slower than the rate at which the matrix erodes inthe aqueous medium, allowing exposure of said surface of the matrix tothe aqueous medium to be controlled.